This is a new SPORE project that evolved from a previously-funded SPORE Pilot project. The overall goal is to develop the Fibroblast Growth Factor Receptor (FGFR) pathway as a therapeutic target in lung cancers. Tyrosine kinase inhibitors (TKIs) targeting EGFR and ALK have greatly impacted the treatment of lung cancers driven by oncogenic forms of these receptor tyrosine kinases (RTKs). Still, a large fraction of lung cancers, especially of non-adenocarcinoma histologies, have no identified driving oncogene and remain an important and unmet clinical need. Our studies have unveiled a role for an FGFR pathway as an oncogene driver in NSCLC cell lines of diverse histologies. FGFR-dependency occurs independently of gain-of-function mutations, although FGFR1 gene amplification and/or copy number gain have recently been described in squamous lung cancers. In addition, rare somatic mutations in FGFR2 and FGFR3 have been reported in lung cancers, although their potential as oncogene drivers has not been defined. FGFR1 gene copy number is being employed as a pre-selection marker in early phase trials of the FGFR-specific TKIs, AZD4547 and BGJ398. While we will further explore FGFR1 copy number gain, our preclinical findings reveal that other predictive biomarkers (FGFR1 mRNA and protein expression) may more accurately identify FGFR-dependent, and therefore FGFR-specific TKI sensitive, lung cancers. Specifically, we have shown that FGFR activity depends on expression of FGFR1 and co-expression of the ligands, FGF2 or FGF9, thereby establishing an autocrine mechanism to drive increased FGFR activity. We will test the hypothesis that an FGF-FGFR1 autocrine pathway serves as a frequent oncogenic driver across all histologies of lung cancers and that specific biomarkers beyond FGFR1 gene copy number will serve as predictive biomarkers of lung cancer patients likely to respond to FGFR-selective TKIs. To test this hypothesis, we will complete the following specific aims. Specific Aim 1: Define biomarkers that accurately identify the subset of lung cancers bearing activated FGFR pathways. Specific Aim 2: Use optimized biomarker selection strategies to conduct a phase II clinical trial with the FGFR-active TKI, ponatinib in lung cancer patients. Specific Aim 3: Identify mechanisms of acquired resistance to FGFR-specific TKIs. Successful completion of this project will exert high impact on overall lung cancer treatment by unveiling a novel and substantial subset of lung tumors that are not presently identifiable through simple mutation screening nor targetable by an approved therapeutic.